ClinVar Miner

Submissions for variant NM_000138.5(FBN1):c.364C>T (rs137854467)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000029732 SCV000052385 pathogenic Marfan syndrome 2011-08-18 criteria provided, single submitter curation Converted during submission to Pathogenic.
GeneDx RCV000181647 SCV000233950 pathogenic not provided 2018-08-30 criteria provided, single submitter clinical testing The R122C pathogenic variant in the FBN1 gene has been reported in multiple individuals with Marfan syndrome or ectopia lentis (Stahl-Hallengren et al., 1994; Black et al., 1998; Loeys et al., 2001; Comeglio et al., 2002; Jin et al., 2007; Jin et al., 2008; Hung et al., 2009; Zadeh et al., 2011; Wang et al., 2013; Li et al., 2014; Castro et al., 2017). This variant has segregated with FBN1-related phenotypes in several families (Stahl-Hallengren et al., 1994; Black et al., 1998). Additionally, the R122C variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server).The R122C variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species and in silico analysis predicts this variant is probably damaging to the protein structure/function. Finally, the R122C variant introduces a cysteine residue within an EGF-like domain of the FBN1 gene, which may affect disulfide bonding and is predicted to alter the structure and function of the protein.
Invitae RCV001201375 SCV000544955 pathogenic Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection 2020-09-09 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 122 of the FBN1 protein (p.Arg122Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is not present in population databases (rs137854467, ExAC no frequency). This variant has been reported in the literature to segregate with disease in two families (PMID: 8040326, 9452085), as well as in multiple unrelated individuals affected with ectopia lentis and/or Marfan syndrome (PMID: 17679947, 12446365, 25053872, 21932315, 22772377, 21895641, 11700157). ClinVar contains an entry for this variant (Variation ID: 16440). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: Deleterious; PolyPhen-2: Probably Damaging; Align-GVGD: Class C0). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics RCV000620673 SCV000738914 pathogenic Cardiovascular phenotype 2017-07-28 criteria provided, single submitter clinical testing The p.R122C pathogenic mutation (also known as c.364C>T), located in coding exon 4 of the FBN1 gene, results from a C to T substitution at nucleotide position 364. The arginine at codon 122 is replaced by cysteine, an amino acid with highly dissimilar properties, and is located in the EGF-like #02 domain. The majority of FBN1 mutations identified to date have involved the substitution or generation of cysteine residues within cbEGF domains (Vollbrandt T et al. J Biol Chem. 2004;279(31):32924-32931). This particular alteration has been detected in numerous unrelated individuals with ectopia lentis (EL) and/or Marfan syndrome (MFS) (e.g., Loeys B et al. Arch. Intern. Med. 2001;161:2447-54; Comeglio P et al. Br J Ophthalmol. 2002;86:1359-62; Jin C et al. Mol. Vis. 2007;13:1280-4; Hung CC et al. Ann. Hum. Genet. 2009;73:559-67; Li J et al. Mol. Vis. 2014;20:1017-24). In addition, this alteration has been reported to segregate with disease in three families (Ståhl-Hallengren C et al. J. Clin. Invest. 1994;94:709-13; Black C et al. Hum. Mutat. 1998;Suppl 1:S198-200; Zadeh N et al. Am. J. Med. Genet. A. 2011;155A:2661-8). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV000626614 SCV000747315 pathogenic High palate; Arachnodactyly; Lens subluxation; Aortic dissection 2017-01-01 criteria provided, single submitter clinical testing
Blueprint Genetics RCV000181647 SCV000927817 pathogenic not provided 2018-07-20 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001000178 SCV001156669 pathogenic not specified 2018-08-13 criteria provided, single submitter clinical testing The FBN1 c.364C>T; p.Arg122Cys variant (rs137854467) has been reported in multiple families with clinical symptoms suggestive of Marfan syndrome, and is strongly associated with ectopia lentis (Black 1998, Comeglio 2002, Jin 2007, Loeys 2001, Stahl-Hallengran 1994). It is reported in ClinVar as pathogenic (Variation ID: 16440) and is absent from general population databases (1000 Genomes Project, Exome Variant Server, and Genome Aggregation Database), indicating it is not a common polymorphism. The variant changes an arginine in an EGF-like domain into a cysteine residue, which meets the revised Ghent nosology criteria of a causative Marfan syndrome variant (Loeys 2010). Based on available information, this variant is considered to be pathogenic. References: Black C et al. Correlation of a recurrent FBN1 mutation (R122C) with an atypical familial Marfan syndrome phenotype. Hum Mutat. 1998; Suppl 1:S198-200. Comeglio P et al. Identification of FBN1 gene mutations in patients with ectopia lentis and marfanoid habitus. Br J Ophthalmol. 2002; 86(12):1359-62. Jin C et al. Novel FBN1 mutations associated with predominant ectopia lentis and marfanoid habitus in Chinese patients. Mol Vis. 2007; 13:1280-4. Loeys B et al. Genotype and phenotype analysis of 171 patients referred for molecular study of the fibrillin-1 gene FBN1 because of suspected Marfan syndrome. Arch Intern Med. 2001; 2001 Nov 12;161(20):2447-54. Loeys B et al. The revised Ghent nosology for the Marfan syndrome. J Med Genet. 2010; 47(7):476-85. Stahl-Hallengren C et al. An extra cysteine in one of the non-calcium-binding epidermal growth factor-like motifs of the FBN1 polypeptide is connected to a novel variant of Marfan syndrome. J Clin Invest. 1994; 94(2):709-13.
Clinical Genetics Karolinska University Hospital,Karolinska University Hospital RCV000181647 SCV001450112 pathogenic not provided 2014-11-05 criteria provided, single submitter clinical testing
OMIM RCV000017902 SCV000038181 pathogenic Marfan syndrome, atypical 1994-08-01 no assertion criteria provided literature only
Center for Medical Genetics Ghent,University of Ghent RCV000029732 SCV000786986 likely pathogenic Marfan syndrome 2017-11-07 no assertion criteria provided clinical testing

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